Advancements in enzyme discovery and protein engineering have accelerated development of green, efficient synthetic routes to complex molecules and broadened implementation of biocatalysis for scalable manufacture of pharmaceutical intermediates.

(S)-3-isobutyl-γ-aminobutyric acid (S-Pregabalin API), is a generic drug for the treatment of epilepsy and neuralgia. It has been previously synthesized via kinetic resolution and re-racemization under harsh conditions, which is inefficient and not eco-friendly.

Herein, we describe the development of an enantioselective desymmetrization of 3-isobutylglutarimid utilizing an evolved D-hydantoinase to produce the Pregabalin Intermediate (IM) (R)-3-isobutyl glutaric acid monoamide en route to S-Pregabalin. Three rounds of computer-guided directed evolution were implemented towards improved activity, enantioselectivity and reduced substrate/product inhibition, providing a fi nal variant that enables the full conversion of 240 g/L substrate into Pregabalin IM with excellent enantiomeric excess (ee) of >99.5%. The promising results demonstrated an economical and sustainable synthesis of S-Pregabalin starting from a prochiral substrate using an evolved D-hydantoinase.

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